The present invention relates to novel benzenesulphonamide compounds, their method of preparation and their therapeutic use.
These novel compounds have an antagonist action towards bradykinin and are useful in therapeutics, particularly for the treatment of pain and inflammation, and especially in the treatment of asthma, cerebral traumatic shock and allergic rhinitis.
It is known that one of the possibilities for treatment of certain pathologies of painful and/or inflammatory character (such as asthma, rhinitis, septic shock, dental pain, etc.) is to inhibit the action of certain hormones such as bradykinin or kallidin. In reality, these peptide hormones are involved in a large number of physiological processes, some of which are closely associated with these pathologies.
Although at present no product having this mode of action is commercially available yet, many studies have been undertaken in order to understand the mode of action of kinins and in particular of bradykinin and its homologues, then to create compounds capable of being bradykinin-receptor antagonists. Among the numerous publications relating to these studies, mention may be made of Pharmacological Reviews Vol. 44 no. 1, pages 1-80 (1992) and Biopolymers (Peptide Science) vol. 37 pages 143-155 (1995).
Bradykinin is a peptide hormone formed of 9 amino acids (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) and kallidin is a peptide hormone (Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) which contains a supplementary amino acid (Lys) with respect to bradykinin. It is known that prior studies have made it possible to obtain peptides which interact with the bradykinin receptors: some such as bradycor (CP.0127 from the company Cortech), icatibant (HOE 140 from the company Hoechst) [xe2x80x9cbradycorxe2x80x9d and xe2x80x9cicatibantxe2x80x9d are international non-proprietary names (INN)] or alternatively NPC 17761 (from the company Scios-Nova) have an inhibitory action on the binding of bradykinin to its B2 receptor. Recent publications cite other peptides capable of having a bradykinin-antagonist action towards its B2 receptor; among these it is possible to mention, for example, WO-A-97/09347, WO-A-97/09346, U.S. Pat. Nos. 5,610,140, 5,620,958, 5,610,142 and 5,597,803. In addition, non-peptide compounds have been proposed as antagonists towards the binding of bradykinin to its B2 receptor, especially in EP-A-0596406, EP-A-0622361, U.S. Pat. Nos. 5,578,601, 5,510,380, FR-A-2735128, JP-A-09/040662, FR-A-2737892, WO-A-97/11069, WO-A-97/41104, WO-A-96/13485 and FR-A-2765222. It is additionally known that certain compounds of structure which is more or less related to those of the compounds aimed at in the present application have already been described, especially in DE-A-3617183 and EP-A-0261539, with regard to their possible antithrombotic properties.
There is a need to attenuate or to suppress pain and inflammation in mammals and especially in man.
To satisfy this need, a novel technical solution has been sought which is effective in the treatment of pain irrespective of its origin, especially in the treatment of pain associated with inflammatory or traumatic phenomena.
According to the invention, it is proposed to provide a novel technical solution, which employs, at the level of the bradykinin B2 receptor, competitive binding between (i) bradykinin and related or analogous hormones, and (ii) an antagonist substance, and which requires compounds of benzenesulphonamide type, which are structurally different from the abovementioned known products, and are capable of limiting or substantially inhibiting the binding of bradykinin and analogous hormones to the said bradykinin B2 receptor.
According to this technical solution, the novel compounds bind competitively to the bradykinin B2 receptor without causing the effects of bradykinin on this receptor (these novel compounds are so-called antagonist substances). This results in the appearance of a state analogous to that observed in the absence of bradykinin, namely a decrease in pain, inflammatory reactions and other harmful effects caused by the receptors activated by bradykinin.
In accordance with this novel technical solution, according to a first aspect of the invention, compounds derived from benzenesulphonamide are proposed as novel industrial products; according to a second aspect of the invention, a method of preparation of these compounds is proposed; and according to a third aspect of the invention, a use of these compounds, especially a therapeutic use, as active principles of specialities or medicinal compositions is proposed.
According to the novel technical solution of the invention, a benzenesulphonamide compound is recommended as novel industrial product, which is characterized in that it is chosen from the group formed by:
(i) the compounds of formula I: 
xe2x80x83in which:
Het1 represents a 5-membered nitrogen-containing heterocycle, especially imidazole, pyrazole or triazole,
Het2 represents a 4-, 5- or 6-membered nitrogen-containing heterocycle of structure: 
xe2x80x83in which
R1 represents a hydrogen atom or a hydroxyl, C1-C4 alkoxy, phenoxy, phenylmethoxy, xe2x80x94CH2OH, cycloalkyloxy, cycloalkylalkoxy (where each cycloalkyl fragment is C3-C8 and the alkoxy fragment is C1-C4), xe2x80x94NHxe2x80x94COxe2x80x94CH3, xe2x80x94COxe2x80x94NH2 or xe2x80x94COxe2x80x94NHxe2x80x94CH3 group,
R2 represents a hydrogen atom or a xe2x80x94CH2OH, xe2x80x94CH2xe2x80x94Oxe2x80x94CH3, xe2x80x94CONR3R4, 
R3 represents a hydrogen atom, a C1-C3 alkyl group, a C3-C8 cycloalkyl group, a (C3-C8) cycloalkyl (C1xe2x80x94C3) alkyl group, a phenyl group, or a phenylmethyl group,
R4 represents a hydrogen atom, a C1-C3 alkyl, xe2x80x94(CH2)nxe2x80x94CH2OH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94CH2xe2x80x94NR5R6, 
R5 represents a hydrogen atom, a C1-C3 alkyl, phenyl, phenylmethyl, pyridinyl, pyridinylmethyl, pyridinylethyl, benzoyl, 4-(amino-iminomethyl)benzoyl, xe2x80x94(CH2)mxe2x80x94CH2OH, xe2x80x94(CH2)mxe2x80x94COOH, xe2x80x94(CH2)mCH2xe2x80x94Oxe2x80x94(CH2)mxe2x80x94CH2OH, xe2x80x94COxe2x80x94(CH2)mxe2x80x94COOH, or 
R6 represents a hydrogen atom or a C1-C3 alkyl group, or, R5 and R6 considered together form, with the nitrogen atom to which they are attached, a 5- to 6-membered N heterocycle,
n=1, 2, 3 or 4,
m=1, 2 or 3; and
(ii) their addition salts.
According to the invention, a method of preparation of the compounds of formula I and their addition salts is also recommended.
The use of a bradykinin B2 receptor antagonist substance, chosen from the compounds of formula I of the present invention and their non-toxic addition salts, is likewise recommended for obtaining a medicament intended for human or animal therapeutic use, against pathologies involving bradykinin or its homologues, in particular against pain, especially in the treatment or prevention of pathologies associated with inflammatory or painful states, and against severe traumatic shock, in particular cerebral traumatic shock.
In the general formula I of the compounds of the invention, C1-C3 alkyl group is understood as meaning a methyl, ethyl, propyl or 1-methylethyl group.
C1-C4 alkoxy group is preferentially understood here as meaning the methoxy, ethoxy, propoxy, butoxy, 1-methylethoxy and 1,1-dimethylethoxy groups. C3-C8 cycloalkyl group is understood as meaning the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, and (cycloalkyl)alkyl groups are understood as meaning especially the cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl and cyclohexylethyl groups.
When a group such as R5 comprises a heterocycle, for example pyridine, and the position of substitution is not specified, it must be understood that the bond with the heterocycle can be made with any of the substitutable members.
5- to 6-membered NR5R6 heterocycle is understood as meaning a pyrrolidine, piperidine, piperazine or morpholine ring, and more particularly a 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or 1-morpholinyl group.
The heterocycle Het1, which has five members, comprises one or more heteroatoms. Advantageously, it comprises 1 to 4 nitrogen members. As represented by the formula I above, Het1 is linked by its nitrogen member or one of its nitrogen members to position 4 of the quinoline.
The heterocycle Het2 is linked by its nitrogen member to the sulphur atom of the group SO2 to form the sulphonamide function.
When, on the heterocycle Het2, the substituent R2 is not a hydrogen atom, the carbon of the ring which carries the substituent R2 can have an S or R configuration. In this case, the compounds according to the invention can be of indeterminate configuration (that is to say a mixture of the R and S isomers) or, preferably, one of the R or S isomers, or, preferentially, the S isomer. In the same way, the substituent R1, when it is not hydrogen, introduces an asymmetric centre and can be found in an indeterminate configuration, or determined R or S configuration, the xe2x80x9ctransxe2x80x9d configuration with respect to the R2 group being preferred.
xe2x80x9cAddition saltsxe2x80x9d are understood as meaning the acid addition salts obtained by reaction of a compound of formula I in its non-salified form with an inorganic acid or an organic acid. The inorganic acids preferred for salifying a basic compound of formula I are hydrochloric, hydrobromic, phosphoric and sulphuric acids. The organic acids preferred for salifying a basic compound of formula I are methanesulphonic, benzenesulphonic, maleic, fumaric, oxalic, citric, lactic, tartaric and trifluoroacetic acids.
Among the compounds according to the present invention, those are preferred in which the heterocycle Het1 is a 1-(1H)-imidazolyl group. The compounds are likewise preferred in which the heterocycle Het2 comprises a 2(S)-pyrrolidinecarboxamide group, 
and more particularly when
R3 represents a hydrogen atom or a C1-C3 alkyl group, and
R4 represents a C1-C3 alkyl group, a xe2x80x94(CH2)nxe2x80x94CH2xe2x80x94NR5R6 group, a pyridinylmethyl group or a 
xe2x80x83group, and
R5 represents a C1-C3 alkyl group, a xe2x80x94(CH2)mxe2x80x94CH2OH group, a (2-pyridinyl)methyl group or a 4-(aminoiminomethyl)benzoyl group,
R6 represents a methyl group or forms, with R5 and the nitrogen to which they are bonded, a 5- or 6-membered saturated heterocycle.
xe2x80x9cAmbient temperaturexe2x80x9d is understood as meaning a temperature of the order of 15 to 25xc2x0 C., and xe2x80x9ctemperature close to ambient temperaturexe2x80x9d as meaning a temperature of approximately 0 to 40xc2x0 C.
A general method of preparation of the compounds of the formula I, which is recommended according to the invention, comprises: according to a first variant A, the steps consisting of:
(1) reacting an 8-hydroxyquinoline derivative of formula II: 
xe2x80x83in which:
Het1 represents a five-membered nitrogen-containing heterocycle comprising in total 1, 2, 3 or 4 nitrogen atoms and M represents an alkali metal, especially sodium or potassium,
with a compound of formula III: 
xe2x80x83in which:
X represents a halogen atom, preferably a bromine atom, and
R1 represents a hydrogen atom or an OH group, an alkoxy group or a phenoxy group,
in an anhydrous solvent such as, for example, dimethylformamide, at a temperature of between 0 and 50xc2x0 C., for 0.5 to 10 hours, in order to obtain a compound of formula IV: 
xe2x80x83in which:
Het1 and R1 retain the same meaning as previously;
(2) hydrolysing the ester function of the compound of formula IV thus obtained according to step (1) above, especially by reaction with an aqueous solution of sodium hydroxide, in a miscible solvent such as, for example, dioxane, at a temperature of the order of 20 to 60xc2x0 C. and for 1 to 5 hours, in order to obtain, after acidification, a compound of formula V: 
xe2x80x83in which:
Het1 and R1 retain the same meaning as above;
(3) reacting the compound of formula V thus obtained with an amine of formula:
HNR3R4xe2x80x83xe2x80x83(VI)
xe2x80x83in which:
R3 represents a hydrogen atom or a C1-C3 alkyl group,
R4 represents a hydrogen atom, a C1-C3 alkyl, xe2x80x94(CH2)nxe2x80x94CH2OH, xe2x80x94(CH2)nxe2x80x94COOR11, xe2x80x94(CH2)nxe2x80x94CH2xe2x80x94NR5R6, 
R5 represents a C1-C3 alkyl, xe2x80x94(CH2)mxe2x80x94CH2OH, xe2x80x94(CH2)mxe2x80x94COOR11, xe2x80x94(CH2)mxe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)mxe2x80x94CH2OH group, or an amino-protecting group such as, for example, a 1,1-dimethylethoxycarbonyl (BOC) group, (R5 and R6 not simultaneously being amino-protecting groups),
R6 represents a C1-C3 alkyl group or an amino-protecting group, for example of the BOC type,
R11 represents a protecting group of the acid function, which is easily hydrolysable such as, for example, the t-butyl (or 1,1-dimethylethyl) group,
n=1, 2, 3 or 4,
m=1, 2 or 3,
in an appropriate solvent, in particular dichloromethane, in the presence of activators such as, in particular, 1-hydroxy-7-azabenzotriazole (HOAT) and 1-[3-(dimethylaminopropyl)-3-ethy]carbodiimide hydrochloride (EDCI), at a temperature close to ambient temperature (0-40xc2x0 C., preferably 10-35xc2x0 C.), for 2 to 50 hours, in order to obtain a compound of formula: 
xe2x80x83in which
Het1, R1, R3, R4 keep the same meaning as previously; and
(4) if necessary, reacting the compound of formula VII thus obtained in order to remove the amino- or acido-protecting groups in such a way as to replace these groups by a hydrogen atom, for example by reaction of the said compound VII with trifluoroacetic acid in order to remove an amino-protecting group of the BOC type or in order to remove an acido-protecting group of the t-butyl type, in such a way as to obtain the compound of formula I: 
xe2x80x83in which:
Het1, R1, R3 and R4 keep the same meaning as above, with the exception of the protecting groups replaced by hydrogen atoms; then,
(5) if necessary, reacting the compound of formula I thus obtained with an acid in order to obtain the corresponding acid addition salt;
according to a second variant B consisting of:
(1) reacting a compound of formula I such as obtained in step (4) of variant A above, 
xe2x80x83in which:
Het1 represents a 1-imidazolyl group, a 1-pyrazolyl group or a 1-(1,2,4-triazolyl) group,
R3 represents H, or a C1-C3 alkyl group,
R4 represents a group which carries a primary or secondary amine function chosen from: xe2x80x94(CH2)nxe2x80x94CH2xe2x80x94NHR6 or 
where R6 represents H or an alkyl group and n represents 1, 2, 3 or 4, with a halogenated compound of formula: Yxe2x80x94(CH2)mxe2x80x94CH2OR13, Yxe2x80x94(CH2)mxe2x80x94COOR11, or Yxe2x80x94(CH2)mxe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)mxe2x80x94CH2OR13,
where
Y is a halogen, preferentially Br or I,
m represents 1, 2 or 3
R11 is an acido-protecting group, such as, for example, t-butyl, and
R13 is a protecting group of the alcohol function, in particular the acetyl group,
in a solvent such as, for example, dimethylformamide or acetonitrile, in the presence of an agent with alkaline character, such as, for example, potassium carbonate, at a temperature close to ambient temperature and for 5 to 20 hours, in order to obtain the compound of formula VII: 
xe2x80x83in which:
R3 represents H or a C1-C3 alkyl group,
R4 represents a xe2x80x94(CH2)nxe2x80x94CH2xe2x80x94NR5R6 or 
xe2x80x83group where
R5 represents group: xe2x80x94(CH2)mxe2x80x94CH2OR13, xe2x80x94(CH2)mxe2x80x94COOR11, or xe2x80x94(CH2)mxe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)mxe2x80x94CH2OR13,
Het1, R6, R11 and R13 keep the same meaning as above;
(2) carrying out a deprotection reaction of each alcohol or acid group in order to replace the R13 and R11 groups by a hydrogen atom, and to thus obtain the corresponding compounds of formula I;
(3) if necessary, reacting the compound of formula I thus obtained with an inorganic or organic acid in order to obtain the corresponding salt;
according to a third variant C, the steps consisting of:
(1) reacting the acid chloride of formula VIII: 
xe2x80x83in which:
X represents a halogen, preferentially bromine,
with a heterocyclic derivative corresponding to the formula: 
xe2x80x83where:
R1 represents H, OH, alkoxy, phenoxy, phenylmethoxy, CH2OH, C3-C8 cycloalkyloxy or cycloalkylalkoxy where the cycloalkyl fragment is C3-C8 and the alkoxy fragment C1-C4,
R2 represents H, or a xe2x80x94CH2OH, xe2x80x94CH2OCH3, xe2x80x94CONH(CH2)nCH2NR5R12, xe2x80x94CONH(CH2)nCH2OH, xe2x80x94CONH(CH2)nCOOR11 or 
n=1, 2, 3 or 4,
R5 represents H or an alkyl group,
R11 represents an acido-protecting group, and
R12 represents an amino-protecting group,
in a solvent such as, for example, acetonitrile, in the presence of a base such as, for example, potassium carbonate or triethylamine, at a temperature close to ambient temperature, for 10 to 30 hours, in order to obtain a compound of formula IX: 
xe2x80x83in which:
Het2 represents a 
xe2x80x83group,
and X, R1, R2, R11, R12 and n keep the same meaning as above;
(2) reacting the compound of formula IX thus obtained with an 8-hydroxy-quinoline derivative of formula II: 
xe2x80x83in which:
Het1 represents a 5-membered nitrogen-containing heterocycle comprising 1, 2, 3 or 4 nitrogen atoms and M represents an alkali metal, in particular sodium or potassium,
under conditions analogous to those employed in step (1) of the preceding variant A, in order to obtain a compound of formula X: 
xe2x80x83in which:
Het1 and Het2 retain the same meaning as above;
(3) if necessary, carrying out a deprotection reaction, for example by the action of trifluoroacetic acid, in order to replace each R11, or R12 protecting group of the acid or amine functions by a hydrogen atom, in order to obtain a compound of formula I: 
xe2x80x83in which:
Het1 retains the same meaning as above, and
Het2 represents a 
R1 has the same meaning as above,
R2 represents a xe2x80x94CH2OH, xe2x80x94CH2OCH3, xe2x80x94CONH(CH2)nCH2NHR5, CONH(CH2)nCH2OH, xe2x80x94CONH(CH2)nCOOH or 
n=1, 2, 3 or 4, and
R5 represents H or an alkyl group; and
(4) if necessary, reacting the compound of formula I thus obtained with an acid in order to obtain the corresponding salt.
The invention will be better understood on reading (i) examples of preparation and (ii) results of pharmacological tests carried out with the compounds according to the invention, which will follow. Of course, both these elements together are not limiting but are given by way of illustration.
In the case of compounds having an asymmetric carbon in their structure, the absence of particular indication or the comment (R,S) signifies that racemic compounds are concerned; in the case of compounds having chirality, this is indicated immediately following the indexation of the substituent carried by the said asymmetric carbon; the (R) or (S) signs are then used, in accordance with the Cahn, Ingold and Prelog rules. The nomenclature used in the examples is that recommended by Chemical Abstracts: thus certain derivatives of L-proline can become, after reaction of the acid function with an amine, derivatives of 2(S)-pyrrolidinecarboxamide.
A solution of 0.7 g (3.11xc3x9710xe2x88x923 mol) of 8-hydroxy-4-[1H-imidazol-1-yl]-2-methylquinoline is prepared in 20 ml of dimethylformamide (DMF) and 0.11 g (3.42xc3x9710xe2x88x923 mol) of 75% sodium hydride in oil is added. After 10 minutes with stirring at ambient temperature, 1.47 g (3.42xc3x9710xe2x88x923 mol) of the methyl ester of N-[3-(bromomethyl)-2,4-dichlorophenylsulphonyl]-L-proline are added. After 15 hours with stirring at ambient temperature, the reaction mixture is hydrolysed on iced water and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and then concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel eluting with the aid of a toluene/propanol mixture (95/5; v/v). 1.07 g of the expected product are thus obtained in the form of a beige solid (yield=68%).
M.p.=100xc2x0 C.
[xcex1]27D=xe2x88x9214.4xc2x0 (c=0.33; CH3OH)
1.6 ml (1.6xc3x9710xe2x88x923 mol) of a normal solution of sodium hydroxide in water are added to a solution of 0.44 g (0.763xc3x9710xe2x88x923 mol) of the compound obtained according to Preparation I in 30 ml of dioxane. The reaction mixture is heated to gentle reflux for 8 hours and the solvent is then driven off under reduced pressure. The residue is taken up again in water and the solution is gently acidified to pH 4.5 with the aid of a solution of hydrochloric acid. The expected acid precipitates. The precipitate is filtered, washed with water on the filter and dried at 40xc2x0 C. under reduced pressure. 0.36 g of the expected product is thus obtained in the form of white powder (Yield=89%).
M.p.=172xc2x0 C.